This is Laboratory Program #5 led by Phil Crews (Department of Chemistry and Biochemistry at the U.C. Santa Cruz). The project entitled, Genetic Materials from marine-Derived Microorganisms as New Anti- cancer Leaders, will explore the potential marine derived materials in combinatorial biosynthesis and combinatorial biology. A library of cultured marine-derived microorganisms will be used for combinatorial biology. A group of seven lead structures are candidates to be explored in combinatorial biosynthetic work. The goal of both approaches is to discover new bioactive natural product anti-cancer chemotherapy leads. The aims of the project are divided into categories as follows: 1. To construct a library of marine-derived microorganisms as a source of genomic DNA for combinatorial biology. 2. To base the microorganism library on marine sponge-derived: fungi, myxobacteria and actinomycetes. 3. To engage in combinatorial biosynthesis studies by exploring genomic DNA from organisms that are a source of UCSC library compounds, especially latrunculin A and swinholide A. 4. To employ mechanism-dependent assays on microorganism extracts to assess the progress of combinatorial biology and biosynthesis. 5. To efficiently isolate secondary metabolites from active extracts guided by high throughput screens. 6. To initiate scale-up reisolation by reculture of recombinant microorganisms for further study in the preclinical models of our consortium grant. 7. To complete the total structure elucidation of active compounds. 8. To obtain patient coverage for important new active compounds.